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Existing animal models of acute pancreatitis (e.g., cerulein, choline-deficient ethionine-supplemented diet) do not resemble gallstone pancreatitis as the etiologies are not analogous. Distal pancreatic duct ligation (PDL) more closely resembles early events in gallstone pancreatitis. We recently developed a novel murine model of PDL-induced acute pancreatitis associated with substantial mortality. Using this model, we previously showed that specific inhibition of the stress kinase ERK with in vivo gene modulation significantly improves survival. In the present study we determine the cause of death in our murine model by serial examination of multiple parameters in three groups: a) Acute pancreatitis group had PDL; b) Hepatic obstruction group had bile duct ligation (BDL) without PDL; c) Sham operation group. The mice were observed for 15 days post-operatively. BDL and Sham controls had no mortality. Close to 100% mortality was seen in PDL-induced acute pancreatitis with most deaths occurring between day 2 and day 4. Characteristics of mice with acute pancreatitis included the following (ANOVA; P<0.05): ERK activation in the pancreas and distant organs; pancreatic neutrophil infiltration and acinar cell necrosis maximal on day 2; increased plasma IL-1β and TNF-α levels on day 2, that peaked on day 3, in parallel with worsening hypotension and bradycardia; bronchoalveolar lavage (BAL) fluid neutrophil count and IL-1β level, and plasma aspartate aminotransferase (AST) level, also peaked on day 3; pulmonary neutrophil infiltration and plasma creatinine level peaked on day 4.. Liver injury evidenced by raised AST after hepatic obstruction was exacerbated by PDL. Increased plasma IL-1β and TNF-α on day 2 after BDL subsided thereafter. Although BDL was also associated with pulmonary neutrophil infiltration it was not associated with increased IL-1β or neutrophils in BAL fluid. BDL-induced renal tubular damage was not associated with raised plasma creatinine. Our findings indicate that the high mortality rate seen in PDL-induced acute pancreatitis in mice is associated with progressive systemic increase of inflammatory cytokine levels, cardiovascular instability, acute lung injury, liver injury, and renal dysfunction, suggesting that systemic inflammation with multiorgan failure is the proximate cause of death in this experimental model. Lung and renal injury as observed by morphology after hepatic obstruction alone is not associated with systemic inflammation or death. In conclusion, systemic inflammation with multiorgan dysfunction causes death in pancreatic duct ligation-induced acute pancreatitis in mice. This experimental model is a useful analogy of severe gallstone pancreatitis to investigate disease pathogenesis and to evaluate novel therapeutic strategies.